Indole synthesis via rhodium catalyzed oxidative coupling of acetanilides and internal alkynes

Article abstract of DOI:10.1021/ja806955s

The oxidative synthesis of highly functionalized indoles from simple anilines and internal alkynes mediated by a rhodium(III) catalyst is described. Good yields are obtained for a variety of aniline substrates, and good regioselectivity is obtained for the more sterically accessible position when meta-substituted anilines are used. Symmetrical and unsymmetrical alkynes react efficiently with high (>40:1) C2/C3 regioselectivity when aryl/alkyl substituted alkynes are used. Copyright

Full text of DOI:10.1021/ja806955s

Published on Web 11/12/2008
Indole Synthesis via Rhodium Catalyzed Oxidative Coupling of Acetanilides
and Internal Alkynes
David R. Stuart, Me´gan Bertrand-Laperle, Kevin M. N. Burgess, and Keith Fagnou*
Center for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa, Ottawa, Canada
Received September 2, 2008; E-mail: keith.fagnou@uottawa.ca
The prevalence of indoles in bioactive molecules1 has prompted
the development of many useful methods for their preparation.2 Despite
advances, most of these techniques rely heavily on substrate preacti-
vation, and very few employ readily available anilines as starting
materials.3 Transition metal catalyzed processes are illustrative,4
commonly requiring ortho-halogenated anilines as starting materials
thus adding cost5 and reducing the breadth of readily available starting
materials. A major advance in the minimization of substrate preacti-
vation in indole synthesis was recently described by Glorius involving
the condensation of simple anilines with 1,3-dicarbonyl compounds
followed by Pd(II)-catalyzed oxidative cyclization.4m Similarly, Gagne´,
Lloyde-Jones, and Booker-Milburn have described an efficient indoline
synthesis via Pd(II) catalyzed coupling of N-arylureas with activated
dienes.6 Herein we describe the realization of a different approach,
namely a rhodium catalyzed oxidative coupling of N-acetyl anilines
and alkynes, as well as preliminary mechanistic studies.
revealed that the presence/absence of chloride anions and the choice
of solvent exert a dramatic impact on reaction outcome.13 For example,
the addition of silver triflate to sequester the chloride ligands increases
the yield 5-fold (entry 2). A solvent screen revealed that the yield could
be further increased to 55% by using tert-amyl alcohol (1,1-dimeth-
ylpropanol) (entry 6), and a second assay of silver salts revealed that,
with 10 mol% silver hexafluoroantimonate, a 79% isolated yield of
3a could be obtained as one regioisomer14 (entry 9). The reaction time
could also be significantly shortened since 3a can be isolated in 69%
yield even after 5 min of reaction (entry 10). Conversely, if 1 equiv
of LiCl is added to the reaction mixture, product formation is
completely inhibited, adding additional weight to the observation that
chloride anions exert a negative role on catalyst activity (Table 1, entry
11).
Both electron-rich (3b, 3h, and 3i) and -deficient (3c and 3d)
acetanilides participate in good yield (Table 2). A chloride substituent
Based on the known ability of N-acetyl anilines to undergo ortho-
metalation,7 and the ease with which N-acetyl indoles may be
deprotected, N-acetylaniline 1a was selected along with 1-phenyl-1-
propyne 2a for reaction development. Extensive experimentation with
a variety of Pd(II) catalysts8 failed to produce indole 3a, instead giving
small amounts of Heck and multiple Heck-type additions. Similarly,
Wilkinson’s catalyst, which has been shown to induce similar reactivity
with 1,2-diaryldiazines,9 gave none of the desired product. A low but
promising outcome was obtained, however, with [Rh(Cp*)Cl2]2 in
conjunction with a stoichiometric Cu(II) oxidant, a catalyst system
recently employed by Satoh and Miura10 and by Jones11 for other
reactions initiated via cyclometalation.12 Under these conditions, small
amounts of 3a (∼3% yield) could be detected by GCMS analysis of
the crude reaction mixture (Table 1, entry 1). Continued optimization
Table 2. Acetanilide Scope in the Rhodium Catalyzed Oxidative
Indole Synthesisa,b
Table 1. Reaction Developmenta
entry
additive (mol%)
solvent
time (h)
GCMS yield (%)
1
2
3
4
5
6
7
8
none
DMF
DMF
DMA
NMP
mesitylene
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
16
16
16
16
16
16
16
16
1
3
15
18
0
40
55
53
74
AgOTf(10)
AgOTf(10)
AgOTf(10)
AgOTf(10)
AgOTf(10)
AgBF4(10)
AgSbF6(10)
AgSbF6(10)
AgSbF6(10)
LiCl(100)
a Conditions: Acetanilide (1 equiv), alkyne (1.1 equiv), [Cp*RhCl2]2
(2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2 ·H2O (2.1 equiv), t-AmOH
(0.2 M), 120 °C, 1 h. b Isolated yields are reported above. c Allowed to
react for 3 h. d Minor isomer 1-acetyl-4-methoxy-3-methyl-2-phenyl-
indole was isolated in 9% yield (see Supporting Information).
9
10
11
86, 79b
65b
<1%
0.1
16
is tolerated (3e), as are ortho-substituents (3f and 3g). When a meta-
substituent is present, reaction is preferred at the more sterically
accessible position (3i and 3j). A variety of other internal alkynes may
also be employed including symmetrically substituted compounds (aryl:
3k; alkyl: 3l) (Table 3). When two different alkyl groups are present
a Conditions: Acetanilide (1 equiv), alkyne (1.1 equiv), [Cp*RhCl2]2
(2.5 mol%), additive, Cu(OAc)2 ·H2O (2.1 equiv), solvent (0.2 M), 120
°C, specified time. b Isolated yield.
9
16474 J. AM. CHEM. SOC. 2008, 130, 16474–16475
10.1021/ja806955s CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Alkyne Scope in the Rhodium Catalyzed Oxidative Indole
which the two potential metallated aniline regioisomers undergo
subsequent indolization. These observations as well as a more detailed
mechanistic evaluation and a greater evaluation of scope are underway.
Synthesisa,b
Acknowledgment. Dedicated to Prof. Tomislav Rovis (Colo-
rado State University) on the occasion of his 40th birthday. We
thank NSERC, the Research Corporation, the Sloan Foundation,
the ACS (PRF AC), Merck Frosst, Merck Inc., Amgen, Eli Lilly,
Astra Zeneca, and Boehringer Ingelheim for financial support.
D.R.S. thanks NSERC for a postgraduate scholarship (PGS-D), and
K.M.N.B. thanks NSERC for an undergraduate summer research
award.
Supporting Information Available: Detailed experimental proce-
dures, characterization data for all new compounds, and computational
details. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) A Beilstein search yielded >45 000 results for indoles with biological
activity.
a Conditions: Acetanilide (1 equiv), alkyne (1.1 equiv), [Cp*RhCl2]2
(2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2 ·H2O (2.1 equiv), t-AmOH
(0.2 M), 120 °C, 1 h. b Isolated yields are reported above. c Minor
isomer 3-n-hexyl-2-methylindole was isolated in 28% yield (see Sup-
porting Information).
(2) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875.
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as in the reaction of 2-nonyne, a 2:1 regioselectivity is observed for
the formation of 3m where the larger n-hexyl substituent is situated at
C2. As observed with 2a, other aryl-alkyl disubstituted alkynes also
react with high regioselectivity (3n, 3o, and 3p). Heterocyclic
substituents, such as a thiophene (3o) and an indole (3p), may also be
present. Important from a potential application perspective, we have
verified that the acetyl moiety is very easily removed under mild
conditions (KOH or K2CO3 in MeOH/DCM at room temperature) to
provide the free N-H indole.15
To probe the reaction mechanism, d5-acetanilide 1a was subjected
to the standard reaction conditions and the reaction was stopped at
low conversion to reveal significant deuterium loss at the ortho-
positions of the unreacted 1a as well as on the product 3a (Scheme
1). In the absence of Rh catalyst, no reaction and no loss in deuterium
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Arai, S.; Nishida, A. Synlett 2004, 907. (j) Nazare, M.; Schneider, C.;
Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526.
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Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2008,Early
View.
(5) ortho-Iodoaniline is $1070/mol, whereas aniline is $12/mol.
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(7) For recent examples in direct arylation, see: (a) Kalyani, D.; Deprez, N. R.;
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Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. For
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Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.;
van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (d) Zaitsev,
V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156 For recent examples
in oxidative biaryl formation, see: (e) Li, B.-L.; Tian, S.-L.; Fang, Z.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115. (f) Brasche, G.; Garcia-
Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207.
Scheme 1. Mechanistic Studies
(8) Only unreacted acetanilide (1a) and trace amounts of a multiple alkyne
insertion product previously observed by Heck appeared in the GCMS
trace. Wu, G.; Rheingold, A. L.; Heck, R. F. Organometallics 1986, 5,
1922.
(9) Aulwurm, U. R.; Melchinger, J. U.; Kisch, H. Organometallics 1995, 14,
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N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47,
4019.
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12414.
(12) For the use of this complex in the cleavage of other stong bonds, see: Taw,
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(13) A similar effect has been observed in rhodium catalyzed carbonylation
reactions. See: Grushin, V. V.; Marshall, W. J.; Thorn, D. L. AdV. Synth.
Catal. 2001, 343, 161.
(14) In the reaction yielding 3a the regioselectivity is >40:1 by GCMS.
(15) All yields for deacetylation were equal to or greater than 90%, and reaction
times were between 15 min to 1 h. Please see Supporting Information for
specific conditions and representative examples.
are observed. This may arise from a fast and reversible arene
metalation/proto(deutero)demetalation step prior to cross-coupling with
the alkyne. Interestingly, when nonsymmetrical aniline 1i (which
undergoes indolization at the more sterically accessible ortho-position)
is allowed to react in d1-tert-amyl alcohol as the solvent and stopped
at early conversions, more deuteration is actually observed at the more
sterically hindered ortho-position (50%) than at the eventual site of
indole formation (21%). This may indicate that the regioselectivity is
controlled not by the site of aniline rhodation but by the ease with
JA806955S
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J. AM. CHEM. SOC. VOL. 130, NO. 49, 2008 16475